# The Role of Canonical and Non-canonical Autophagy in B Cell Immunity

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $458,604

## Abstract

B cells play a central role in human health by protecting us against infections through their ability to produce
high-affinity antibodies and long-lived memory cells capable of antigenic recall. Perturbations in B cell function
can not only lead to lowered ability to fight infections and inefficacy of vaccinations, but also to conditions such
as leukemia, and autoimmune diseases. Thus, understanding the molecular mechanisms that contribute to
optimal B cell function is extremely important for the generation of new therapeutics and vaccination strategies.
The major goal of this proposal is to study how autophagy, a lysosomal degradative pathway with numerous
physiological and pathophysiological roles, shapes B cell immunoresponses. The induction of canonical
autophagy typically requires the downregulation of the biosynthetic kinase, mTORC1. However, in B cells upon
BCR stimulation both autophagy and mTORC1 activity are simultaneously upregulated, suggesting that B cell
autophagy is likely to be mTORC1 independent. Our lab has recently shown that there is a switch from basal
canonical autophagy in naïve, antigen-inexperienced B cells to an unconventional, mTORC1-independent, non-
canonical activity in the germinal center (GC) B cells upon antigenic stimulation. GCs are the determinants of
high affinity, class switched antibody generation, and therefore the study of the mechanisms that drive these
high-quality immunoresponses is vitally important in the development of next-generation vaccines, therapeutic
monoclonal antibodies and in the treatment of autoimmune diseases.
 Our working hypothesis is that non-canonical autophagy is important during B cell proliferation and will be
relevant to GC biology affecting antibody quality, while canonical autophagy is important for long-lived memory
cells and plasma cells influencing antibody durability. To test this hypothesis, we will evaluate GC and long-term
immune responses in mice bearing genetic ablations of novel autophagy genes that we know affect the balance
between canonical and non-canonical autophagy, namely Wipi1, Wipi2 and Rubicon. We will also determine the
mechanisms by which the deletions of these genes affect antigen presentation and in eliciting T cell help. Finally,
because autophagy intersects with mitochondrial integrity and metabolism, we will determine how these gene
deletions control the capacity of GC B cells, memory and plasma cells to regulate ROS production, mitochondrial
homeostasis and metabolic status and potentially influence B cell fate.
 We envision that the successful completion of these experimental aims will not only provide a better
understanding of B cell function, but also mechanistic insights into how to modulate autophagy to affect humoral
immunity – augment it in cases such as immunosenescence, or downregulate it in instances of autoimmune
diseases.

## Key facts

- **NIH application ID:** 9864028
- **Project number:** 5R01AI135052-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Facundo Damian Batista
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $458,604
- **Award type:** 5
- **Project period:** 2018-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9864028

## Citation

> US National Institutes of Health, RePORTER application 9864028, The Role of Canonical and Non-canonical Autophagy in B Cell Immunity (5R01AI135052-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9864028. Licensed CC0.

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